A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfillment of the requirements for the degree of Masters in Medicine (Internal Medicine) Johannesburg 2017 / Background Glomerular disease is a frequent and important cause of renal dysfunction. Current data on the patterns of glomerular disease in South Africa is lacking. The aim of this study was to characterize the prevalence and nature of presentation of primary glomerular disease at Charlotte Maxeke Johannesburg Academic Hospital. Materials And Methods This single center, retrospective observational study was performed on adult native renal biopsies over a 10 year period from 2001 - 2010. A total of 1495 native renal biopsies were reviewed. After exclusion of common secondary causes, the results of 194 patients with primary glomerular disease were evaluated. Results The most frequent primary glomerular disease was FSGS (29.8%) followed by MN (19.5%), MPGN (18%), MCD (17%) and IgAN (3%). Nephrotic range proteinuria (60.5%) and unexplained renal dysfunction (24.2%) were the most common indications for biopsy. There was a 59.4% male predominance. From the 73.9 % of patients of African descent, 34.1% presented with FSGS. The majority of patients (62.9%) were aged between 18-49 years with 30.3% of them presenting with FSGS. FSGS presented with a median creatinine 183.5 [101 - 476] mmol/l and mean UPCR (0.89 ± 0.66) g/mmol. There were no statistically significant differences in albumin, haemoglobin and triglycerides between the glomerular disease subtypes. The highest urine leucocytes and dysmorphic red cells were from the IgAN subtype. Most patients, 56.8% had no casts observed, and 39.1% were hypertensive. No change in the pattern of glomerular injury was observed over the course of the study. Conclusion Glomerular pathology is more common in younger patients. FSGS is more common than other glomerular pathologies in our setting; which may partly be due to local biopsy practices and patient demographics. Clinical parameters do not adequately predict biopsy findings. / MT2017

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Myh9 is a gene that encodes for non-muscle myosin IIA (NM-IIA), an actin cytoskeleton component and protein involved in cell movement and adhesion in most cells, including podocytes. Autosomal dominant mutations in NM-IIA have been associated with focal segmental glomerular sclerosis (FSGS) in patients with the mutation. Furthermore, a strong association has been discovered between genetic variation in the Myh9 region on chromosome 22, and the increased risk of chronic kidney disease in African Americans. Later studies by Johnstone et al. using podocyte specific, Myh9 KO in mice showed that knocking out this gene alone was not enough to cause proteinuria or glomerular sclerosis. However, in our own laboratory we have found that when these same mice are exposed to models of glomerular hypertension, glomerular damage is promoted. This damage was preceded by evidence of podocyte loss in urine and tissue. Podocyte loss is a hallmark of kidney disease, and while it is known to occur in vivo, the mechanisms behind this phenomenon are unknown. It is believed that increase in glomerular capillary blood pressure is likely to be a strong contributing factor. Based on these findings, we hypothesized that the mechanical strain in the form of stretch, occurring during hypertension, may act as a second hit to Myh9 ablation in podocytes, causing changes in podocytes ability to adhere to the glomerular basement membrane (GBM), ultimately leading to the pathology seen in patients. To test this, we knocked down Myh9 in immortalized mouse podocytes cultured on flexible silicon membranes and exposed them to mechanical stretch for 24hrs. Cell adhesion was evaluated via cell attachment assays. Cell morphology and focal adhesions (FA) were examined using immunofluorescence and quantified using imageJ. Our results showed a significant decrease in transduced cells attached to the membrane after stretch, as well as an increase in FA size and number in cells that underwent stretch, except in the Myh9 knockdown. Cells with Myh9 knockdown also showed marked increase in area, with a decrease in FA size and number after exposure to stretch. These results support our hypothesis that Myh9 mutations may be a contributing factor to podocyte loss in patients with hypertension and chronic kidney disease.

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